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Preliminary Results: A randomised, prospective, multicenter phase III trial of adjuvant chemotherapy with gemcitabine vs. observation in patients with resected pancreatic cancer - CONKO*-001 -. - PowerPoint PPT Presentation
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Preliminary Results:
A randomised, prospective, multicenter phase III trial of adjuvant chemotherapy with gemcitabine vs.
observation in patients with resected pancreatic cancer
- CONKO*-001-
P. Neuhaus, H. Oettle, S. Post, K. Gellert, K. Ridwelski, H. Schramm,
C. Zülke, G. Fahlke, J. Langrehr, L. Roll, H. RiessCharitè - Universitätsmedizin Berlin - Campus Virchow Klinikum;
Ruprecht-Karls-Universität, Mannheim; Oskar-Ziethen-Krankenhaus, Berlin; Otto-von-Guericke-Universität, Magdeburg; Wald-Klinikum, Gera;
Universität Regensburg, Regensburg; AIO; CAO; Deutsche Krebsgesellschaft e.V.
*CHARITÉ ONKOLOGIE:Clinical studies in GI cancers
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 Rationale
Prognosis in disease free survival with pancreatic cancer is still poor
Median survival after resection is 11 - 25 months
Long term survival (>5 years) is 8 - 21percent
Bakkevold (1993); Klinkenbijl (1999); Gastrointestinal Study Group (1985, 1987); Neoptolemos (2004)
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 Study Design
Resected pancreatic cancer368 patients
Stratification: R; T; N
Follow up every 8 weeks
Gemcitabinefor 6 months
Observationfor 6 months
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 Disease Monitoring
Gem
Obs
Gemcitabine 1000 mg/m²: d1, 8, 15; q 4 weeks
Observation: d1; q 4 weeks
Randomisati
on
Follow up every 8weeks
Gem
Ultrasoundafter week 8
Ultrasoundafter week 16
CT Scanafter week 32
Obs
Gem
Obs
Gem
Obs
Gem
Obs
Gem
Obs
Gem
Obs
CA 19-9 CA 19-9 CA 19-9 CA 19-9 CA 19-9 CA 19-9
4 weeks 4 weeks 4 weeks 4 weeks 4 weeks 4 weeks
CA 19-9
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 Endpoints
Primary Endpoint Disease free survival (DFS)
Secondary Endpoint Overall survival (OS) Toxicity
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 Entry Criteria
Histologically proven resected pancreatic carcinoma Standard operation No measurable disease No prior chemo- or radiotherapy No active infection Karnofsky performance status 50% Adequate hematologic, renal and hepatic function CA 19-9, CEA < 2.5 ULN Start with adjuvant therapy within 6 weeks after resection Written informed consent
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 Statistics
Hypothesis: Significant increase in disease free survival (DFS) of
at least 6 months due to chemotherapy with gemcitabine
Statistics: Kaplan-Meier estimates und two-tailed log-rank test
with significance level of 0.05 and a power of 90%
Sample size: 368 pts – 184 pts per treatment arm (1:1 ratio) including an estimated drop out rate of up to 20%
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 Recruitment and Analysis
Time of recruitment: 7/98 - 12/04
Recruited patients: 368 Recruiting centres: 88 (Germany, Austria)
Date of Analysis: March 2005
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 RecruitmentP
atie
nts
Patients per m
onth
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 Patient Disposition
368 patients enrolled7/98 - 12/04
182 pts. for Observation
179 eligible* pts. (96%) 177 eligible* pts. (97%)
* 7 excluded Patients:
4 pts. lost to follow up
1 pt. without histological proven pc
1 pt. with persistent disease after resection
1 pt. with another tumor disease
* 5 excluded Patients:
3 pts. lost to follow up
2 pts. with another tumor disease
186 pts. for Gemcitabine
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 Patient Characteristic
Characteristic Chemotherapy(N=179)
Observation(N=177)
Days to randomisation
Median (interquartile range) 22 (15 - 32) 24 (15 - 34)
Age - years
Median (range) 62 (32 - 84) 61 (36 - 81)
Sex – no. (%)
Female 74 (41%) 79 (45%)
Male 105 (59%) 98 (55%)
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 Tumor Characteristic
Characteristic Chemotherapy(N=179)
Observation(N=177)
<T3 25 (14%) 25 (14%)T
3 + 4 154 (86%) 152 (86%)
negative 52 (29%) 48 (27%)N
positive 127 (71%) 129 (73%)
1 10 (5%) 9 (5%)
2 103 (58%) 95 (54%)
3 62 (35%) 69 (39%)G
unknown 4 (2%) 4 (2%)
R0 145 (81%) 149 (84%)R
R1 34 (19%) 28 (16%)
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 Toxicities WHO Grade III+IV
Chemotherapyn (%) of cycles
Observationn (%) of cycles
WHO Grading III IV III IV
Leucopenia 19 (2.6) 0 0 0
Anemia 7 (0.9) 0 1 (0.2) 0
Thrombocytopenia 5 (0.7) 2 (0.3) 0 0
Bleeding 0 0 0 0
Infection 2 (0.3) 0 2 (0.3) 0
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 Toxicities WHO Grade III+IV
Chemotherapyn (%) of cycles
Observationn (%) of cycles
WHO Grading III IV III IV
Bilirubin 1 (0.1) 0 1 (0.2) 1 (0.2)
Transaminases 6 (0.8) 1 (0.1) 4 (0.7) 1 (0.2)
Alk. Phosphatases 1 (0.1) 0 4 (0.7) 0
Serum Creatinine 0 0 1 (0.2) 0
Proteinuria 0 0 0 0
Hematuria 0 0 0 0
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 Toxicities WHO Grade III+IV
Chemotherapyn (%) of cycles
Observationn (%) of cycles
WHO Grading III IV III IV
Nausea 12 (1.6) 0 1 (0.2) 0
Diarrhea 9 (1.2) 0 3 (0.5) 0
Oedema 4 (0.5) 1 (0.1) 1 (0.2) 0
Pulmonary Function 2 (0.3) 0 0 0
Pain 3 (0.4) 0 10 (1.7) 0
Diverse 1 (0.1) 1 (0.1) 0 0
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
months
847260483624120
cum
ula
tive
dis
ea
se f
ree
su
rviv
al
100%
75%
50%
25%
0%
CONKO-001 Kaplan Meier Disease Free Survival
Chemotherapy with gemcitabine
median: 14.21 months (95% CI, 12.86; 15.57)41 % patients censored (+)
Observation
median: 7.46 months (95% CI, 6.80; 8.11)22 % patients censored (+)
Log Rank: p=0.001
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 Disease Free Survival
Chemotherapymedian (months)
Observationmedian (months)
P – value(log rank)
Negative 19.3 11.2 < 0.05N
Positive 13.1 7.0 < 0.05
R0 14.0 7.9 < 0.05R
R1 14.5 5.5 < 0.05
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 Kaplan Meier Survival
months
847260483624120
cum
ula
tive
su
rviv
al
100%
75%
50%
25%
0%
Chemotherapy with gemcitabine53 % patients censored (+)
Observation45 % patients censored (+)
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 Preliminary Data Summary
Toxicity of gemcitabine in adjuvant therapy is low
Treatment with gemcitabine results in an improvement in disease free survival
Favourable overall survival with chemotherapy(no comparative calculations done; 49% of patients
censored)
Improved longterm (3- and 5-year) survival expected
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 Conclusions
Treatment with gemcitabine in patients with resected pancreatic cancer results in improved disease free survival as compared to observation
Gemcitabine may become the standard of care for adjuvant treatment of pancreatic cancer
Charité - Universitätsmedizin Berlin - Campus Virchow Klinikum
CONKO-001 Top recruiting centres
Charité, Universitätsmedizin Berlin, Campus Virchow-Klinikum - Germany Klinikum Mannheim gGmbH, Universitätsklinikum, Fakultät für Klinische Medizin Mannheim - Germany Paritätisches Krankenhaus Lichtenberg, Oskar-Ziethen-Krankenhaus, Berlin - Germany Otto-von-Guericke-Universität Magdeburg, Medizinische Fakultät - Germany SRH Wald-Klinikum Gera gGmbH - Germany Klinikum der Universität Regensburg - Germany Eberhard-Karls-Universität Tübingen, Universitätsklinikum Tübingen - Germany Universitätsklinikum Bonn, Medizinische Fakultät der Rheinischen Friedrich-Wilhelms-Universität - Germany Klinikum Bremen Mitte gGmbH - Germany Städtisches Klinikum Magdeburg, Standort Altstadt - Germany Klinikum der Friedrich-Schiller-Universität zu Jena - Germany Klinikum Nürnberg Nord - Germany Klinikum und Fachbereich Medizin der Johann-Wolfgang-Goethe Universität Frankfurt am Main - Germany Praxis Dr. Schlag, Würzburg - Germany Universitätsklinikum Freiburg - Germany DRK Krankenhaus Luckenwalde - Germany Praxis Drs. med. Mayr & Strohbach, Berlin - Germany Praxis Drs. med. Günther & Sauer, Potsdam - Germany Praxis Dr. Hauch, Erfurt - Germany Humaine Klinikum Bad Saarow - Germany Henriettenstiftung Hannover - Germany Charité, Universitätsmedizin Berlin, Campus Berlin-Buch - Germany Diakoniekrankenhaus Rotenburg (Wümme) - Germany Gemeinnützige Salzburger Landeskliniken Betriebsgesellschaft mbH - Austria Israelitisches Krankenhaus in Hamburg - Germany Städtisches Krankenhaus Hildesheim GmbH - Germany Praxis Dr. von Grünhagen, Cottbus - Germany Städtisches Klinikum Dessau - Germany